This Program of 15 years explores the reproductive roles and signaling mechanisms of protein/peptide hormones and growth factors originally characterized by virtue of their neuroendocrine actions; focus is on inhibin and activin and their receptors and GnRH. Project 1 (Vale): Which discovered the first activin receptor during the current funding period will examine the nature and signaling of the complex between activin and the two types of activin receptors; will clone and characterize the inhibin receptors; and will study the regulation of the activin and inhibin receptors in the pituitary. Project 2 (C.Rivier): Will investigate the modulation of hypothalamic GnRH production by activin and inhibin and will continue to probe the interactions between the reproductive and immune systems. Project 3 (J.Rivier): Will deign conformationally constrained analogs of GnRH for biological and structural analyses and will continue to develop and provide potent antagonists for clinical studies. Project 4 (Fischer): Will design and produce recombinantly, mutated activins probe requirements for receptor recognition and signaling. Project 5 (Choe): Will use X-ray crystallography to solve the tertiary structure of activin-activin receptor(s) ectodomain complexes, activin- follistatin complexes and avidin-biotinylated GnRH complexes. Core 1: Provides administrative support. Core 2: Provides characterized polyclonal antisera towards activins, inhibins and their receptors and radioimmunoassays for pituitary and gonadal hormones. Core 3 (Fisher): Prepares recombinant proteins needed in large quantities and characterizes recombinant proteins with regards to primary sequence, arrangement of disulfide bridges and phosphorylation. Core 4 (Rivier): Prepares and characterizes synthetic peptides for use as antigens or biological studies. The program thus brings together a diversity of skills and approaches to address fundamental questions of neuroendocrine control and signaling. Because of the importance of GnRH, inhibin and activin in fertility control and the pathogenesis of reproductive and other disorders, it is likely that these basic studies will continue to yield practical benefits.